The objective of this project is to generate IL-33 deficient mice and to subject them to initial characterization. IL-33 is a recently identified member of the interleukin-1 family, which includes IL-1- alpha, IL-1-beta and IL-18. In November 2005, IL-33 was identified as the extracellular ligand for an interleukin-1 receptor family member, ST2 (official name IL1RL1). The rapidly expanding literature on IL- 33 shows that as an extracellular ligand for the ST2 receptor, IL-33 has potent immunomodulary functions in allergy and immune diseases. IL-33 is identical to a molecule discovered in 2003 called Nuclear Factor of High Endothelial Venules (NF-HEV), a nuclear factor highly expressed in the endothelium with transcriptional repressor properties. Endogenous nuclear IL-33 is expressed in endothelial and epithelial cells representing an addition mode of IL-33 regulation in chronic inflammation. Prior to the identification of IL-33 as the ligand for the ST2 receptor, the ST2 receptor had been associated with inflammatory asthma, pulmonary fibrosis, vascular diseases, sepsis and heart disease in clinical and experimental studies. While an ST2 receptor knockout mouse is currently available, it cannot address the roles of IL-33 in bone marrow progenitor cell egress and expansion, regulation of IL-33/ST2L signaling, and nuclear functions of IL-33 in the regulation of chronic inflammation. Based on the viability of ST2 receptor knockout mice, we anticipate that IL-33 knockout mice will be viable. An IL-33 knockout mouse, which is currently not available, has a high potential to identify novel regulatory mechanisms in human chronic inflammatory diseases. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE The objective of this project is to generate IL-33 deficient mice. IL-33 is a member of the interleukin-1 family that was recently identified as the extracellular ligand for an interleukin-1 receptor family member, ST2. The rapidly expanding literature on IL-33 shows that as an extracellular ligand for the ST2 receptor, IL-33 has potent immunomodulary functions in allergy and immune diseases. An IL-33 knockout mouse, which is currently not available, has a high potential to identify novel regulatory mechanisms in human pulmonary and chronic inflammatory diseases.